ORLANDO — New results from the Action to Control Cardiovascular Risk in Diabetes trial lend further support to the growing consensus that attempting to normalize blood glucose levels in patients with longstanding type 2 diabetes and cardiovascular risk factors is not beneficial and may be harmful.
Two new studies on microvascular complication outcomes from ACCORD—showing mixed results—and an update on cardiovascular outcomes at 5 years (see sidebar on p. 12) were presented at the meeting.
The ACCORD trial randomized 10,251 adults with type 2 diabetes to either intensive glycemic control with a target hemoglobin A1c of less than 6.0%, or standard therapy aiming for HbA1c values of 7.0%-7.9%. The intensive arm was stopped early in February 2008, after a median follow-up of 3.7 years, because of a 22% higher all-cause mortality in the intensive group. Subjects in that arm were then transitioned to standard therapy for the rest of the trial, which also included blood pressure and lipid control arms. (N. Engl. J. Med. 2008;358:2545-59).
Dr. Faramarz Ismail-Beigi presented the results of a prespecified analysis of microvascular outcomes data, which were published simultaneously (Lancet 2010 [doi:10.1016/S0140-6736(10)60576-4]). At the time of that transition and at study end, the intensive glycemia and standard control groups did not differ in the prespecified primary composite outcome of advanced nephropathy and diabetic eye complications, nor in a second composite end point that added a peripheral neuropathy outcome.
At the end of the study, 10.9% of the intensive group and 11.5% of the standard treatment group met the first composite end point, and 38.2% and 40.0%, respectively, met the second, said Dr. Ismail-Beigi, professor of medicine and chief of clinical and molecular endocrinology at Case Western Reserve University, Cleveland.
However, microvascular renal outcomes based on urinary measures were significantly reduced in the intensive glycemic therapy group. Intensive glycemia therapy led to a 21% reduction in the development of microalbuminuria at the time of transition. This effect was attenuated to 15% at study end, but remained statistically significant, Dr. Ismail-Beigi reported.
For diabetes-related eye events, three-line worsening of visual acuity was more common in the standard group than in the intensive group at both transition and study end (20.7% vs. 19.1%). Cataract extraction was also significantly reduced, by 21%, in the intensive group, compared with standard group at study end. Other diabetes-related eye outcomes did not differ between the groups.
Peripheral neuropathy was less common in the intensive group than in the standard group at study end (55.6% vs. 58.6%), he said.
Results of the prespecified ACCORD Eye study were presented by Dr. Emily Y. Chew. She and her colleagues evaluated a subset of 2,856 ACCORD participants from among the 5,518 subjects with dyslipidemia who were also randomized to simvastatin plus either fenofibrate or placebo, and another 4,733 randomized to intensive blood pressure control (systolic less than 120 mm Hg) or standard BP control (less than 140 mm Hg). The ACCORD Eye study subgroup was evaluated for the effects of these interventions at 4 years.
At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemic treatment vs. 10.4% with standard therapy (adjusted odds ratio 0.67). With fenofibrate, progression occurred in 6.5%, compared with 10.2% for placebo (OR 0.60). Both of those differences were statistically significant.
However, there was no significant difference in progression with intensive BP therapy compared to standard therapy, said Dr. Chew, deputy director of epidemiology and clinical research at the National Eye Institute, Bethesda, Md.
Rates of moderate vision loss did not differ significantly between groups, Dr. Chew reported. These results were also published simultaneously with the presentation (N. Engl. J. Med. 2010 June 29 [doi:10.1056/NEJMoa1001288]).
Dr. Ismail-Beigi stressed that the ACCORD findings can only be interpreted in the context of patients resembling the study population: Older, with longstanding diabetes and additional cardiovascular risk factors. But, for a patient who's younger, with newly diagnosed diabetes and a long life expectancy, “I would try to get them to normal in all parameters as long as I could do it safely,” he said in an interview. “The key here is multifactorial treatment, paying attention to all risk factors simultaneously.”
Disclosures: ACCORD was funded by the National Heart, Lung, and Blood Institute. Dr. Chew is a government employee with no conflicts of interest. Dr. Ismail-Beigi has received travel support from NHLBI and did not disclose any other relationships.
CV Outcomes Consistent
Dr. Hertzel C. Gerstein presented the 5-year cardiovascular update at the meeting.
For the primary outcome measure—the first occurrence of a major cardiovascular disease event, specifically nonfatal MI, nonfatal stroke, or cardiovascular death—rates from the beginning of the study until 5 years were 2.08%/year with intensive treatment versus 2.25%/year with standard treatment. As at the time of transition, the difference was nonsignificant, with a hazard ratio of 0.91, compared with 0.90 at the time of transition, noted Dr. Gerstein, professor of medicine and director of the division of endocrinology and metabolism at McMaster University, Hamilton, Ontario.
But also similar to the time the glycemia arm of the trial was stopped, there was still a significantly greater risk for all-cause mortality among those who had been in the intensive treatment group, with rates of 1.53% versus 1.27% per year for intensive versus standard treatment. The hazard ratio at 5 years was 1.19, compared with 1.21 at the time of transition, Dr. Gerstein reported.
Cardiovascular death at study end was also significantly greater in the previous intensive treatment group (0.73% vs. 0.56%/year), whereas nonfatal MI rates again went in the opposite direction, being more common in those in the standard group (1.42% vs. 1.18% per year). The reason for this is not known, he said.
“No clinical trial is going to tell you how to manage the person sitting across the table from you,” Dr. Gerstein noted. “You know if you have someone at high cardiovascular risk, if you try to get them to perfectly normal A1c, you're probably doing more harm than good.”
Dr. Gerstein stated that he has served as a consultant, given scientific talks, and/or his institution has received research, educational, and CME grants from the following companies: Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, Eli Lilly, Bristol Myers Squibb, AstraZeneca, Roche, Boehringer Ingelheim, and Bayer.
—Miriam E. Tucker
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